Core–shell hybrid nanogels for integration of optical temperature-sensing, targeted tumor cell imaging, and combined chemo-photothermal treatment
Introduction
The ability of a nanoparticle (NP) drug delivery vector that can provide long-circulation with adequate drug loading, illuminate the targeted object, and intelligently sense and dose the pathological zones will enable major advancements in medical science and disease treatment [1], [2], [3], [4], [5], [6]. Noble metal such as Ag and Au NPs possess unique optical properties, including surface-enhanced, distance-/refractive index-dependent spectroscopic properties, and anti-photobleaching properties [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], thus have been extensively explored for optical markers in biodiagnostic imaging [17], [18], [19], [20], [21]. With the strong absorptions in the near-infrared (NIR) region and efficient photo-to-heat conversions (photothermal effect) [22], [23], [24], [25], [26], [27], nanostructured noble metal NPs have been developed for combined imaging and photothermal therapy [28], [29], [30], [31], [32]. However, these phototherapeutic systems deliver only the heat to the tumorigenic region without any drugs. It is expected that the therapeutic efficacy will be significantly improved if drugs can be simultaneously delivered with heat or radiation to the tumor site [33], [34], [35], which makes it possible to shorten treatment time or cut dosage.
Recently, drug delivery vectors prepared from noble metal NPs with various surface functionalizations have been explored to conjugate targeting ligands and drug molecules [5], [36], [37], [38], [39], [40], [41], [42]. A key attribute of drug delivery systems is their ability to regulate drug release, minimize side effects, and improve therapeutic efficacy [42], [43]. Generally, these current drug delivery vectors prepared from the monolayer protected noble metal NPs have very low drug loading capacity. In addition, most of the capping agents on the noble metal NPs are insensitive to local environmental change to regulate the drug release, although photoregulated release can be achieved for photosensitive drugs covalently attached to the monolayer protected metal NPs [36], [37], [38]. In order to overcome these problems, Yoo et al. [1], [44] have fabricated polymer–metal multilayer half-shell NPs by depositing Au nanolayers onto the biodegradable poly(lactide-co-glycolic acid) (PLGA) NPs. While the PLGA particles can serve as a drug carrier with high loading capacity, the Au nanolayer can absorb the NIR irradiation for photothermally controlled drug release. Xia et al. [45] developed a platform based on Au nanocages covered with a monolayer of thermo-responsive poly(N-isopropylacrylamide-co-acrylamide) chains. The Au nanocages can absorb the NIR light and convert it to heat, which induces the thermo-responsive polymers to collapse and thus trigger the release of the drug molecules pre-loaded inside the nanocages.
In this work, we aim to develop a class of core–shell structured multifunctional hybrid nanogels to combine targeting, optical sensing of environmental temperature change, fluorescence imaging of cancer cell, adequate drug loading, and controllable drug release into a single NP system. As illustrated in Fig. 1, the spherical hybrid nanogel particle is comprised of Ag–Au bimetallic NP as core, thermo-responsive nonlinear PEG-based hydrogel as shell, and surface hyaluronic acid (HA) chains as targeting ligands. The Ag–Au bimetallic NP core is designed to emit fluorescent light for optical sensing and cellular imaging, as well as absorb and convert the NIR light to heat for photothermal treatment. The nontoxic responsive nonlinear PEG-based gel shell is designed to serve as intelligent drug carriers with high drug loading capacity. The reversible swelling and shrinking of the gel shell in response to temperature change will not only modify the physicochemical environment of the embedded Ag–Au NP core to manipulate the optical properties of core for sensing on local environment, but also change the mesh size of the gel networks to regulate the drug release. The surface HA chains are added to bind cluster determinant 44 (CD44) overexpressed on various tumors for targeting function [46], [47], [48], [49]. We expect that the combination of the functions from the Ag–Au bimetallic NP core and responsive gel shell in the hybrid nanogels will enhance the therapeutic efficacy. Many pathological processes in various tissues and organs are accompanied with local temperature increase by 1–5 °C [50], [51], [52]. This specific temperature increase of the local pathological environment (endogenous activation) can provide a biologically controlled release, while the NIR light can provide orthogonal external thermal stimulus (exogenous activation) for spatiotemporal control of payload release. Thus, the thermo-responsive hybrid nanogels acting as drug carriers may not only provide basal chemotherapy for daily care under the endogenous activation strategy, but also offer fast-acting dosage under exogenous activation strategy, which will enhance our ability to address the complexity of biological systems with remarkable spatial and temporal resolutions.
Section snippets
Materials
All chemicals were purchased from Aldrich. 2-(2-methoxyethoxy)ethyl methacrylate (MEO2MA, 95%), oligo(ethylene glycol)methyl ether methacrylate (MEO5MA, Mn = 300 g/mol) and poly(ethylene glycol) dimethacrylate (PEGDMA, Mn ≈ 550 g/mol) were purified with neutral Al2O3. Temozolomide (TMZ), hyaluronic acid (HA, Streptococcus zooepidemicus), AgNO3, NaBH4, sodium citrate, chloroauric acid trihydrate (HAuCl4∙3H2O), l-ascorbic acid, 0.1 N HCl standard solution, 2,2′-azobis(2-methylpropionamidine)
Synthesis and structure of Ag-Au@PEG–HA hybrid nanogels
The strategy to prepare the multifunctional hybrid nanogels with nonlinear PEG hydrogel as shell and Ag–Au bimetallic NP as core involves the first synthesis of Ag NPs, followed by immobilization of thermo-responsive hydrogel shell on the Ag NP templates, and then a moderate growth of Au nanoclusters on the surface of encapsulated Ag NPs. The size of highly fluorescent Ag NPs can be easily controlled by using a dilute citrate solution [57]. Fig. 2A shows the TEM image of spherical
Conclusion
We have successfully developed a class of multifunctional hybrid nanogels (<100 nm) through coating the Ag–Au NPs (10 ± 3 nm) with the thermo-responsive gel shell based on the nonlinear PEG oligomers for integration of optical temperature-sensing, tumor cell targeting and imaging, and thermo-/photothermal-regulated drug delivery. The targeting macromolecule HA can be semi-interpenetrated into the surface networks of the gel shell at a light penetration depth through the hydrogen bonding between
Acknowledgement
We gratefully acknowledge the financial support from the US Agency for International Development under the US–Pakistan Science and Technology Cooperative Program (PGA-P280422) and the National Science Foundation (CHE 0316078). We also thank Phyllis Langone at the CSI/IBR Center for Developmental Neuroscience for her help with cell culture.
References (73)
- et al.
Multifunctional magnetic nanoparticles for targeted imaging and therapy
Adv Drug Deliv Rev
(2008) - et al.
In-situ immobilization of quantum dots in polysaccharide-based nanogels for integration of optical pH-sensing, tumor cell imaging, and drug delivery
Biomaterials
(2010) - et al.
Photo-thermal tumor ablation in mice using near infrared-absorbing nanoparticles
Cancer Lett
(2004) - et al.
Selective laser photo-thermal therapy of epithelial carcinoma using anti-EGFR antibody conjugated gold nanoparticles
Cancer Lett
(2006) - et al.
Gold nanoparticles in delivery applications
Adv Drug Deliv Rev
(2008) - et al.
Gold nanoparticles with a monolayer of doxorubicin-conjugated amphiphilic block copolymer for tumor-targeted drug delivery
Biomaterials
(2009) - et al.
CD44 is the principal cell surface receptor for hyaluronate
Cell
(1990) - et al.
A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells
Cell
(1991) - et al.
Dissolution-recrystallization mechanism for the conversion of silver nanospheres to triangular nanoplates
J Colloid Interface Sci
(2007) - et al.
Determination of temozolomide in human plasma and urine by high-performance liquid chromatography after solid-phase extraction
J Chromatogr B
(1995)
Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC)
Adv Drug Deliv Rev
Multifunctional nanoparticles for photothermally controlled drug delivery and magnetic resonance imaging enhancement
Small
New generation of multifunctional nanoparticles for cancer imaging and therapy
Adv Funct Mater
Multifunctional inorganic nanoparticles for imaging, targeting, and drug delivery
ACS Nano
Gold nanoparticles in nanomedicine: preparations, imaging, diagnostics, therapies and toxicity
Chem Soc Rev
Assembly-disassembly of DNAs and gold nanoparticles: a strategy of intervention based on oligonucleotides and restriction enzymes
Anal Chem
Encapsulation and growth of gold nanoparticles in thermoresponsive microgels
Adv Mater
Au@pNIPAM colloids as molecular traps for surface-enhanced, spectroscopic, ultra-sensitive analysis
Angew Chem Int Ed
Facile photochemical synthesis and characterization of highly fluorescent silver nanoparticles
J Am Chem Soc
Selective colorimetric detection of polynucleotides based on the distance-dependent optical properties of gold nanoparticles
Science
Gold nanoparticles for the development of clinical diagnosis methods
Anal Bioanal Chem
Design and synthesis of single-nanoparticle optical biosensors for imaging and characterization of single receptor molecules on single living cells
Anal Chem
The use of gold nanoparticles in diagnostics and detection
Chem Soc Rev
Near-infrared gold nanocages as a new class of tracers for photoacoustic sentinel lymph node mapping on a rat model
Nano Lett
Gold and silver nanoparticles in sensing and imaging: sensitivity of plasmon response to size, shape, and metal composition
J Phys Chem B
In vitro and in vivo two-photon luminescence imaging of single gold nanorods
Proc Natl Acad Sci U S A
Two-photon luminescence imaging of cancer cells using molecularly targeted gold nanorods
Nano Lett
Nonbleaching fluorescence of gold nanoparticles and its applications in cancer cell imaging
Anal Chem
Can silver nanoparticles be useful as potential biological labels?
Nanotechnology
Bifunctional Fe3O4–Ag heterodimer nanoparticles for two-photon fluorescence imaging and magnetic manipulation
Adv Mater
Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance
Proc Natl Acad Sci U S A
pH-induced aggregation of gold nanoparticles for photothermal cancer therapy
J Am Chem Soc
Immuno gold nanocages with tailored optical properties for targeted photothermal destruction of cancer cells
Nano Lett
Biomedical applications of shape-controlled plasmonic nanostructures: a case study of hollow gold nanospheres for photothermal ablation therapy of cancer
J Phys Chem Lett
Immunotargeted nanoshells for integrated cancer imaging and therapy
Nano Lett
Cancer cell imaging and photothermal therapy in the near-infrared region by using gold nanorods
J Am Chem Soc
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